Pleasant-tasting aqueous liquid composition of a bitter-tasting drug

ABSTRACT

A liquid pharmaceutical composition is contemplated that comprises a pharmaceutically effective amount of a bitter tasting drug dissolved or dispersed in an aqueous medium that is free of ethanol. That aqueous medium consists essentially of water, about 5 to about 30 weight percent polyvinylpyrrolidone, about 35 to about 55 weight percent of a C 3  -C 6  polyol, about 0.01 to about 0.5 weight percent ammonium glycyrrhizinate and one or more flavorants. The liquid composition is transparent and has a pleasant taste. The bitter tasting drugs claimed herein are vitamin and mineral preparations, trimethoprim, and guaifenesin.

CROSS-REFERENCE TO A RELATED APPLICATION

The present application is a continuation-in-part of U.S. applicationSer. No. 08/692,081, filed Aug. 7, 1996, now U.S. Pat. No. 5,763,449 andclaims priority to PCT/US97/14018, filed Aug. 7, 1997.

TECHNICAL FIELD

This present invention relates to a liquid drug composition, and moreparticularly to a pleasant-tasting aqueous liquid pharmaceuticalcomposition that contains an otherwise bitter-tasting drug.

BACKGROUND ART

Many useful, effective drugs have a bitter taste when dissolved inliquid form or even when administered as pills or tablets. Exemplary ofsuch drugs are acetaminophen, terfenadine, guaifenesin, trimethoprim,prednisolone, ibuprofen, prednisolone sodium phosphate, methacholine,neostigmine, epinephrine, albuterol, pseudoephedrine hydrochloride,diphenhydramine, chlorpheniramine maleate, phenothiazine,chlorpromazine, chlordiazepoxide, amitriptyline, barbiturates,diphenylhydantoin, caffeine, morphine, demerol, codeine, lomotil,lidocaine, salicylic acid, sulfonamides, chloroquine, a vitaminpreparation, minerals and penicillins. These and other bitter-tastingdrugs are consequently usually formatted for oral administration ascoated pills or tablets or as a powder or prills within a capsule sothat the bitter-tasting medicament does not contact the tongue duringoral administration.

Although provision in an above coated tablet or pill form or within acapsule overcomes the problem of offensive taste for several valuablemedicaments for most of the adult population that uses those drugs, manyadults and many children have difficulty swallowing the pills or tabletsor cannot swallow them, and thereby do not benefit from those drugs.Recently issued U.S. Pat. No. 5,455,049 illustrates one technique thatwas successful in overcoming the bitter taste problem associated withorally administered terfenadine.

The disclosure that follows illustrates another, more general solutionto both of the problems of bitter taste and oral administration of asolid dosage form such as a pill or capsule that is applicable to adultsand children that have difficulty swallowing or cannot swallow pills,capsules and the like, as well as an alternative delivery mode for thegeneral population.

BRIEF SUMMARY OF THE INVENTION

A transparent liquid pharmaceutical composition is contemplated by thepresent invention. That composition comprises a pharmaceuticallyeffective amount of a bitter-tasting drug that is dissolved or dispersedin an aqueous medium that is free of ethanol. That aqueous mediumconsists essentially of water, about 5 to about 30 weight percentpolyvinylpyrrolidone (PVP), about 35 to about 55 weight percent of a C₃-C₆ polyol, about 0.01 to about 0.5 weight percent ammoniumglycyrrhizinate and one or more flavorants. The aqueous liquidcomposition is transparent and has a pleasant taste when orallyadministered; i.e., it is free from having a bitter taste that wouldotherwise be associated with the bitter-tasting drug.

In preferred practice, the drug is present in an amount of about 0.5 toabout 5 weight percent and the ammonium glycyrrhizinate is present in aweight ratio relative to the drug of about 1:50 to about 2:1, andpreferably at about 1:50 to about 1:10. Preferably, the PVP is presentat about 5 to about 20, and more preferably at about 7 to about 15weight percent, the drug at about one to about 3 weight percent, withthe glycyrrhizinate present at the before-noted weight ratio to thedrug, and most preferably at a weight ratio to the drug of about 1:20.

The present invention has several benefits and advantages.

One benefit is that a contemplated composition has a pleasant taste thatpermits it to be administered to children without the usually observedreluctance of children to take the bitter-tasting drug.

An advantage of the invention is that the bitter drug-containingcomposition is provided as a liquid to that it can be taken by thosepersons that have difficulty swallowing or cannot swallow usual solidforms of the drug such as a pill, tablet or capsule.

Another benefit of the invention is that a contemplated composition isfree of ethanol so that it can be taken by children to whom anethanol-containing pharmaceutical composition would normally not begiven.

Another advantage of the invention is that a contemplated composition istransparent, homogeneously dispersed and non-settling so that one neednot resuspend the medication within the composition prior to eachadministration and each dose contains a desired amount of themedicament.

Still further benefits and advantages of the invention will be apparentto those skilled in the art from the disclosure that follows.

DETAILED DESCRIPTION OF THE INVENTION

The present invention contemplates a liquid pharmaceutical compositionthat contains a normally bitter-tasting drug as active ingredient. Acontemplated composition nonetheless has at least a pleasant taste ifnot a good taste when administered orally.

The otherwise or normally bitter-tasting drug is dissolved or dispersedin an aqueous medium that is transparent. That is, the composition ofdrug and ingredients other than the flavorant, even if not forming atrue solution, is not cloudy or milky in the aqueous medium. It ispresently not known if the aqueous medium containing the drug and otheringredients is a true solution or a non-settling dispersion, but thatcomposition containing its various constituents discussed hereinafter istransparent as would be a true solution or a colloidal dispersion.

A contemplated pharmaceutical composition is free of ethanol (ethylalcohol). Ethanol is often used in aqueous medicinal compositions as asolvent for the active medicament. However, because of its potentialeffects upon children, ethanol is not utilized in a contemplatedcomposition, or if used is present in an amount of about two percent,and more preferably one percent by volume or less.

A contemplated composition is referred to as having an aqueous medium inthat water is present as a major ingredient.

A pharmaceutically effective amount of a bitter-tasting drug is alsopresent in a contemplated composition as the active ingredient.Exemplary bitter-tasting drugs include acetaminophen, terfenadine,guaifenesin, trimethoprim, prednisolone, ibuprofen, prednisolone sodiumphosphate, methacholine, neostigmine, epinephrine, albuterol,pseudoephedrine hydrochloride, diphenhydramine, chlorpheniraminemaleate, phenothiazine, chlorpromazine, chlordiazepoxide, amitriptyline,barbiturates, diphenylhydantoin, caffeine, morphine, demerol, codeine,lomotil, lidocaine, salicylic acid, sulfonamides, a vitamin preparation,one or more minerals such as an iron salt and admixtures of a vitaminpreparation and one or more minerals, chloroquine and penicillins. Thedetermination of a bitter taste is carried out by standard, well-knownpractices, and is a characteristic often listed along with a descriptionof the drug in texts such as The Merck Index, 11th ed., S. Budavari etal. eds., Merck & Co., Inc., Rahway, N.J. (1989) and Remington'sPharmaceutical Sciences, 18th ed., A. Gennaro ed., Mack Publishing Co.,Easton, Pa. (1990).

A pharmaceutically effective amount of a bitter-tasting drug is aconcentration of the drug, which when present in a predetermined volumeof the composition, provides a therapeutic dosage. It should be apparentthat a pharmaceutically effective amount of a bitter-tasting drug is orcan be different for each drug. In addition, that amount can also differfor the same drug where compositions formulated for children and adultsare contemplated.

Therapeutic dosages of a contemplated bitter-tasting drug are well-knownand are available from the above-noted texts as well as from thePhysicians' Desk Reference, Medical Economics Company, Inc., Oradell,N.J. or Goodman and Gilman's The Pharmacological Basis of Therapeutics,8th ed., Gilman et al. eds, McGraw Hill, Inc., New York, N.Y. (1993).Exemplary therapeutic dosages and therapeutically effective amounts ofexemplary bitter-tasting drugs are provided hereinafter.

Exemplary amounts of active bitter-tasting drug are present at about 0.1to about 10 weight percent, and preferably at about 0.5 to about 5weight percent of the completed composition. The bitter-tasting drug ismore preferably present at about one to about 3 weight percent of thecompleted composition.

In addition to the water and bitter-tasting drug, a contemplatedcomposition also contains about 5 to about 30 weight percentpolyvinylpyrrolidone (PVP), preferably about 5 to about 20 weightpercent, and more preferably about 7 to about 15 weight percent PVP. PVPis commercially available from a number of suppliers under a number ofdesignations. The PVPs sold under the Trademark KOLLIDON® K25, K30 andK90 having weight-average molecular weights of 28,000-34,000,44,000-54,000 and 1,000,000-1,500,000, respectively, are preferred foruse here, with the K25 and K30 being most preferred.

PVP is dissolved or dispersed in the water of the aqueous medium andserves to assist in dissolving or dispersing the bitter-tasting drug inthat medium, as well as masking the flavor of the bitter-tasting drug.The disclosures of Volker Buhler's book, Kollidon, BASFAktiengesellshaft, Ludwigshafen, Germany (1992) teach the use of PVP asboth a solubilization aid for several drugs as well as for masking thebitter taste of acetaminophen. An exemplary formulation for an oral PVP-and acetaminophen-containing composition is provided at page 113, Table81 of the above Buhler text, but to the inventors' knowledge, nocommercial liquid product takes advantage of that combination ofingredients and effects, indicating that those debittering effects areinsufficient to provide a useful product.

A contemplated composition also contains about 35 to about 55 and morepreferably about 45 to about 55 weight percent (as solids ornon-volatile liquids) of a C₃ -C₆ polyol. Exemplary C₃ -C₆ polyolsinclude propylene glycol, glycerin (glycerol), threose, threitol,erythrose, erythritol, ribose, arabinose, lyxose, sorbitol, sorbose,glucose, mannose, galactose, xylose, fructose and the like.

A C₃ -C₆ polyol serves the dual function of being a solvent for thesystem as well as being a bitter flavor masking agent. In one preferredembodiment, a mixture of two or more C₃ -C₆ polyols is utilized. Such apreferred mixture utilizes a C₃ polyol such as glycerin or1,3-propanediol (propylene glycol) and one or more C₆ polyols such asmaltitol NF (a starch hydrolyzate containing about 75 weight percent drysolids of which at least about 50 percent is D-maltitol and about 15percent or less is D-sorbitol and is available under the mark LYCASIN™from Roquette Corp., Gurnee, Ill., fructose such as that available underthe mark KRYSTAR™, from A.E. Staley Mfg. Co., Decatur, Ill. that is soldas an aqueous liquid about 77 weight percent of which is fructose, aswell as sugars such as glucose, xylitol, sorbitol and the like. It isnoted that each maltitol molecule is composed of a plurality of C₆polyols linked together and so is deemed to be a C₃ -C₆ polyol as issucrose. This mixture, when utilized, is typically present at a ratioweight of 1:4 to about 3:5, C₃ to C₆ polyol, as non-volatiles. Inanother preferred embodiment, polyols other than a C₆ polyol constituteless than about 5 weight percent of the total composition.

Surprisingly, the use of the above C₃ -C₆ polyols together with the PVPis not sufficient to suitably mask the bitter taste of thebitter-tasting drug. This fact remains even when further sweeteners suchas sodium saccharin USP present at 0.05-2 weight percent or aspartamepresent at about 0.1 to about 2 weight percent and further flavorantsare admixed with the composition. A further debittering agent is stillrequired to be present.

That further debittering agent is found to be ammonium glycyrrhizinatethat can be present at about 0.01 to about 0.5 weight percent asammonium glycyrrhizinate itself. The ammonium glycyrrhizinate ispreferably present at a weight ratio to the otherwise bitter-tastingdrug of about 1:50 to about 2:1, more preferably about 1:50 to about1:10, and most preferably at weight ratio of about 1:20 ammoniumglycyrrhizinate to drug.

Ammonium glycyrrhizinate is available as a 10 weight percent solution inglycerin or propylene glycol from MacAndrews & Forbes Company of CamdenN.J. under the name MAGNASWEET® MM110 or MM115, and also as a white,amorphous powder as MM150. Ammonium glycyrrhizinate is the monoammoniumsalt of a triterpenoid saponin that consists of an aglycone ofglycyrrhetic acid and a sugar moiety of two glucuronic acid units linkedto each other. This material is said by its manufacturer to be about 50to about 100 times sweeter than sucrose, and is known to be useful inmasking bitterness.

Although ammonium glycyrrhizinate is a known bitterness-masking agent asis PVP, neither material alone or with the before-discussed sweetenersand flavorants is sufficient to mask the bitter taste of a contemplatedbitter-tasting drug. Rather, PVP and ammonium glycyrrhizinate appear topotentiate each other to provide the desired bitterness-masking effect.

The mechanism by which the bitterness-masking is achieved is unknown.However, without wishing to be bound by theory, it is believed that acomplex is formed between the PVP, drug and ammonium glycyrrhizinate,particularly because so little of the glycyrrhizinate is present.

The before-mentioned Buhler, Kollidon, BASF Aktiengsellshaft,Ludwigshafen, Germany (1992) book teaches that PVP forms complexes witharomatic compounds, particularly those drugs also having hydrophilicgroups that can form hydrogen bonds such as carboxyl, hydroxyl and aminegroups. See also, Horn et al., J. Pharm. Sci., 71:1021-126 (1982). Thecontemplated bitter-tasting drugs have one or more rings, most of whichare aromatic, and so it is thought that PVP forms a complex with thebitter-tasting drug. Table 20 at page 40 of Buhler's book listsinteraction constants for several such complexes, although no suchinteraction constant could be determined for trimethoprim, which isquite useful here. See also, Horn et al., J. Pharm. Sci., 71:1021-1026(1982).

Ammonium glycyrrhizinate contains no aromaticity, but has severalhydrophilic groups such as hydroxyls and carboxyl groups and ahydrophobic aglycone portion that can be solvated by the PVP polymericbackbone. It is consequently believed that the three components form apresently undefined complex in the aqueous medium, and that that complexacts to shield taste buds from the bitterness inherently present in thebitter-tasting drug.

As was noted previously, a contemplated composition can also containadditional sweeteners, and flavorants, as well as colorants andthickeners. Flavorants such as bubble gum and chocolate flavors canprovide opacity or translucency to a contemplated composition, while thecomposition other than the flavorant is transparent. Exemplarythickeners include sodium alginate, gelatin or a polyalkylene oxide suchas the polyoxyethylene-polyoxypropylene-polyethylene terpolymeravailable under the name PLURONIC® F68 having an average of 75polymerized ethylene oxide units on either side of 30 polymerizedpropylene oxide units, F-87 having 62 polymerized ethylene oxide unitson either side of 39 polymerized propylene oxide units, or F-88 havingan average of about 97 polymerized ethylene oxide groups on either sideof about 39 polymerized propylene oxide groups that are available fromBASF, Mount Olive, N.J. Conventional preservatives such as sodiumbenzoate NF, methylparaben NF and propylparaben NF can be and preferablyare also present. A contemplated aqueous liquid pharmaceuticalcomposition has a viscosity of 25° C. between that of water and aboutthat of corn syrup at 25° C.

A contemplated composition has a final pH value of about 2 to about 8,and preferably about 3 to about 5, and more preferably about 3.5 toabout 4.5. Sodium hydroxide (1 N) and hydrochloric acid (10 N) or citricacid and sodium citrate are typically used for pH value adjustments andmaintenance.

A contemplated aqueous liquid pharmaceutical composition is readilyprepared. Thus, in an exemplary procedure where a C₃ polyol is utilized,a solution or dispersion of about 30 weight percent PVP is prepared inwater. About one part bitter-tasting drug is slurried with about 5 partsby weight C₃ polyol (glycerin or propylene glycol or both). The twocompositions are admixed and heated to a temperature of about 45° C.with continued agitation. Agitation is continued at that temperatureuntil a clear, non-settling solution or dispersion is formed, whichgenerally takes about 30 minutes. Where no or less than 5 weight percentC₃ polyol is used, the bitter-tasting drug is admixed directly with theaqueous PVP.

The aqueous composition so formed is cooled at a temperature below about30° C. and the ammonium glycyrrhizinate, other C₃ -C₃ polyols,flavorants, colorant if used and remaining ingredients are admixed untila homogenous composition is obtained. These additions are typicallycarried out serially, with admixture to homogeneity between eachadmixture. The pH value is thereafter adjusted as required. The examplesthat follow illustrate these procedures more fully.

BEST MODE FOR CARRYING OUT THE INVENTION EXAMPLE 1

Guaifenesin-containing Syrup

A liquid anti-tussive composition was prepared containing the followingingredients and their amounts.

    ______________________________________    Ingredient             Amount    ______________________________________    Guaifenesin, USP       2.0    g    Polyvinylpyrrolidone   7.5    g    (PVP; K25)    Glycerin, USP          10.0   g    Purified Water, USP    25.0   mL    Sodium Benzoate, NF    0.15   g    Saccharin Sodium, USP  0.50   g    Monoammonium           1.0    g    Glycyrrhizinate (10%).sup.1    Citric Acid            0.25   g    anhydrous, USP    Sodium Citrate, USP    0.384  g    Sodium Alginate, USP   0.2    g    Maltitol Syrup, NF     20.0   g    (75%) solids)    Flavors and Colorants  q.s    Liquid Fructose        q.s.    (77.0-77.5% solids                           100.0  mL    ______________________________________     .sup.1 A 10% solids solution in glycerin or propylene glycol from     MacAndrews & Forbes Co.

The PVP was dissolved or dispersed in 25 mL of purified water. Thesodium alginate was added to that composition and the resultingadmixture mixed until homogeneity to form Phase A.

The guaifenesin and glycerin were mixed to form a smooth slurry as PhaseB. Phase A was then added to Phase B with constant stirring. Thisadmixture was heated to a temperature of 45° C. and that temperature wasmaintained for about 30 minutes with mixing to form Phase C as atransparent composition. Phase C was then cooled to a temperature below30° C.

The citric acid and sodium citrate were dissolved in 5 mL of water toform Phase D. The sodium benzoate and sodium saccharin were similarlydissolved in another 5 mL of water to form Phase E.

Phase D was admixed with Phase C and mixed for about 5 minutes to obtainhomogeneity. Phase E was then similarly admixed with that homogeneouscomposition to form Phase F.

The maltitol was similarly admixed with Phase F to form Phase G to whichthe ammonium glycyrrhizinate was added with another about 5 minutesmixing time being used. The flavors and colorants were then admixed,with a mixing time of about 5 minutes, followed by addition of asufficient amount of liquid fructose to make the desired volume andmixing to homogeneity. The pH value was thereafter adjusted to bebetween 4 and 5 using a citric acid or sodium citrate solution. Thiscomposition provides 100 mg of guaifenesin per 5 mL (teaspoon).

Four differently flavored and colored clear syrups were prepared usingthe before-described ingredients. Those syrups wereorange/vanilla-flavored colorless, vanilla-flavored colorless,chocolate-flavored brown, and gum-fruit-flavored red syrups. The bitterguaifenesin taste was well masked in each syrup.

EXAMPLE 2

Comparative Taste Study

A flavor acceptance study was conducted using a composition of Example 1colored red and flavored with gum-fruit and a commercially availableguaifenesin-containing composition sold under the mark ROBITUSSIN®.Eighty-one children aged between 3 and 6 years (33 boys and 48 girls)were enrolled in the study.

More specifically, the study followed a two-way crossover design, withall subjects evaluating both products at one-half teaspoon for eachproduct. The two products were evaluated on a single study day. Thesequence of products was randomized among subjects. All enrolledsubjects completed all aspects of the study protocol. There were noadverse events reported.

The primary analysis of the ordinal taste scores (1=disliked a lot,2=disliked a little, 3=just OK, 4=liked a little, 5=liked a lot) was ananalysis of variance including factors for dosing sequence, subjectwithin sequence, dose order and product. The effect of sequence wastested using subject (sequence) for error and was not significant. Doseorder and product effects were tested against the residual errorvariance. All tests were performed at the 5% level. A secondary analysistested product preferences using the Sign Test.

The results showed a statistically significant preference (p=0.013) fora syrup of Example 1 (mean=3.42±1.52) compared to ROBITUSSIN®(mean=2.86±1.63) based on the primary analysis of the children's ordinalratings of the flavor. In the secondary analysis, 59.3 percent ofchildren (48/81) stated a preference of the syrup of Example 1 comparedto ROBITUSSIN® (33/81), showing a trend in support of the primaryresults.

The analysis of variance showed no statistically significant effect ofsequence. Dose order, however, did show a statistically significanteffect (p=0.004) on flavor scores: the second product tasted tended tobe rated higher than the first. Thus, mean flavor scores± standarddeviations were 3.03±1.56 for the composition of Example 1 when testedfirst and 3.80±1.38 when tested second for an overall score of3.42±1.52. The commercial ROBITUSSIN® product exhibited scores of2.61±1.70 and 3.13±1.54 when tested first and second, respectively, andan overall score of 2.86±1.63.

EXAMPLE 3

Trimethoprim Oral Liquid #1

An oral liquid pharmaceutical composition was prepared utilizing thefollowing ingredients in the following amounts.

    ______________________________________    Ingredient             Amount    ______________________________________    Trimethoprim, USP      5      kg    Polyvinylpyrrolidone,  50     kg    USP (PVP; K25)    Glycerin, USP          25     kg    Propylene Glycol, USP  52.5   kg    Purified Water, USP    125    kg    Methylparaben, NF      500    g    Propylparaben, NF      250    g    Sodium Benzoate, NF    500    g    Saccharin Sodium, USP  5      kg    Monoammonium           20     kg    Glycyrrhizinate (10%    solids).sup.1    Sorbitol Solution, USP 65     kg    Hydrochloric Acid, NF  1.25   L    Sodium Hydroxide, USP  q.s.    (1 N)    Hydrochloric Acid, USP q.s.    (10 N)    Maltitol Solution, NF  50     kg    (75% solids)    Bubblegum Flavor       2.5    kg    Liquid Fructose        q.s.    (77.0-77.5% solids)                           500    L    ______________________________________     .sup.1 A 10% solids solution in glycerin or propylene glycol from     MacAndrews & Forbes Co.

Here, 110 kg of the purified water was acidified with 1.25 liters of HClto which the trimethoprim was added and mixed until dissolved. The PVPwas admixed with agitation and the agitation continued until ahomogeneous, clear composition was obtained. Most of the propyleneglycol (40 kg) was admixed to homogeneity, followed by admixture of theglycerin. The resulting admixture was heated to a temperature of 45° C.and maintained of that temperature with constant mixing for about 10minutes to form Phase A.

The parabens were dissolved in the remaining 12.5 kg of propylene glycolto form Phase B. The sodium benzoate and sodium saccharin were dissolvedin 15 kg of purified water to form Phase C.

The maltitol was admixed with Phase A for about 5 minutes, at which timethe sorbitol was added followed by another about 5 minutes of stirringto form Phase D. Phase B was admixed with Phase D followed by about 5minutes of stirring to form Phase E, to which Phase C was added andmixed for about 5 minutes to form Phase F. The ammonium glycyrrhizinatewas admixed with Phase F followed by about 5 minutes of stirring to formPhase G to which the bubblegum flavor was added and stirred tohomogeneity. The volume was made up to 500 liters with the liquidfructose, and the resulting composition was stirred to homogeneity. ThepH value of the composition was thereafter adjusted with sodiumhydroxide and/or hydrochloric acid as required to provide a pH value of3.5 to 4.5.

The resulting liquid pharmaceutical composition did not have the bittertaste usually associated with trimethoprim, and provided trimethoprim inan amount of 50 mg/ teaspoon (50 mg/5 mL).

EXAMPLE 4

Trimethoprim Oral Liquid #2

A second trimethoprim-containing oral liquid pharmaceutical compositionwas prepared that contained less than 5 weight percent C₃ polyol; i.e.,only the C₃ polyol contributed by an ammonium glycyrrhizinate solution.That composition had the following ingredients present in the followingamounts.

    ______________________________________    Ingredient             Amount    ______________________________________    Trimethoprim, USP      1.0    g    Polyvinylpyrrolidone,  15.0   g    USP (PVP; K25)    Purified Water, USP    25     mL    Sodium Benzoate, NF    0.15   g    Saccharin Sodium, USP  1.0    g    Monoammonium           4.0    g    Glycyrrhizinate (10%    solids).sup.1    Hydrochloric Acid, NF  0.25   mL    Sodium Hydroxide, USP  q.s.    (1 N)    Hydrochioric Acid, USP q.s.    (10 N)    Maltitol Solution, NF  10     g    (75% solids)    Flavorant              q.s.    Colorant               q.s.    Liquid Fructose        q.s.    (77.0-77.5% soiids)                           100.0  mL    ______________________________________     .sup.1 A 10% solids solution in glycerin or propylene glycol from     MacAndrews & Forbes Co.

For this preparation, the purified water was acidified with the 0.25 mLof hydrochloric acid. The trimethoprim was added to the acidified waterwith stirring over about 5 minutes. The PVP was then added with stirringto homogeneity for about 10 minutes, followed by admixture of themaltitol and stirring for a further 5 minutes time period. The resultingadmixture was then heated to a temperature of 45°-60° C. and maintainedat that temperature with continued mixing until the compositionclarified and no particles could be seen. The heating was then stopped,the composition cooled to below 30° C., and ammonium glycyrrhizinate wasadded. The composition was then mixed for about 5 minutes to form PhaseA.

The sodium benzoate and sodium saccharin were dissolved in about 30 g ofliquid fructose to form Phase B. Phase B was added to Phase A, and theresulting composition was mixed for about 5 minutes, after which theflavorant and colorant were added with another 5 minutes of mixing. ThepH value was adjusted to 3.5-4.5, the composition was made up to a finalvolume of 100 mL using liquid fructose, and the resulting compositionwas stirred for another 5 minutes to form the trimethoprim-containingoral liquid pharmaceutical composition. That composition was homogeneousand clear, and exhibited a pleasant taste, particularly as compared tothe usually bitter taste of trimethoprim, and provided 50 mg oftrimethoprim/5 mL of composition.

EXAMPLE 5

Prednisolone Sodium Phosphate Oral Liquids

Two pleasant-tasting liquids for oral administration containingprednisolone sodium phosphate as active ingredient were preparedcontaining the ingredients and amounts shown in the table below forliquid 1 and liquid 2.

    ______________________________________                    Liquid 1   Liquid 2    Ingredient      (w/v or w/w %)                               (w/v or w/w %)    ______________________________________    Prednisolone Sodium                    0.134      0.403    Phosphate USP    Polyvinylpyrrolidone,                    5.0        5.0    USP (PVP; K25)    Ethanol, USP    1.71       1.71    Purified Water, USP                    20.0       20.0    Sodium Benzoate, NF                    0.15       0.15    Monoammonium    2.0        2.0    Glycyrrhizinate (10%    solids).sup.1    Sorbitol Solution, USP                    10.0       10.0    (70% soiids)    Sodium Hydroxide, USP                     q.s.      q.s.    (1 N)    Citric Acid, USP                    q.s.       q.s.    (50%)    Maltitol Soiution, NF                    q.s.       20.0    (75% solids)    Favorant        0.65       0.75    Liquid Fructose --         q.s.    (77.0-77.5% solids)    ______________________________________     .sup.1 A 10% solids solution in glycerin or propylene glycol from     MacAndrews & Forbes Co.

Purified water, USP was charged into a kettle and agitation of the waterbegun. The Povidone 25, USP was slowly added to the mixing water and theresulting admixture agitated until all of the Povidone 25, USP wasdissolved to form phase one.

Further purified water, USP was added to a separate vessel and stirringof the water begun. To the stirring solution was added PrednisoloneSodium Phosphate, USP, and stirring was continued until all particleswere dissolved to form phase two.

Still further purified water, USP was added to a third vessel and mixingof the water began. Sodium Benzoate, NF was admixed with agitation untilall particles were dissolved to form phase three.

Phase one, phase two and phase three were admixed together withagitation, followed by admixture of the Sorbitol Solution 70%, USP, theMagnasweet, Ethanol, Flavorant, Maltitol solution, NF, and the resultingcomposition diluted qs with liquid fructose. Agitation was continued tohomogeneity. The pH value was measured and adjusted to 7.0 (±0.3) withcitric acid or sodium hydroxide as necessary.

EXAMPLE 6

Oral Liquid Vitamin Preparations

Two pleasant-tasting oral vitamin preparations with iron or vitamin B₁₂were prepared containing the ingredients and amounts shown in the tablebelow.

    ______________________________________                     Liquid 1        Liquid 2    Ingredient       (Amt/100 mL)    (Amt/100 mL)    ______________________________________    Ascorbic Acid, USP                     3.5     g       3.5   g    Thiamine HCl., USP                     0.05    g       0.05  g    Riboflavin Phosphate                     0.06    g       0.06  g    Sodium, USP.sup.1    Niacinamide, USP 0.8     g       0.8   g    Pyridoxine HCl, USP                     0.04    g       0.04  g    Vitamin A Palmitate, USP                     150000  IU      150000                                           IU    Vitamin E Acetate, USP                     500     IU      500   IU    Vitamin D3       40000   IU      40000 IU    Vitamin B12, USP --              0.2   mg    Dried Ferrous Sulfate, USP                     1.0     g       --    Purified Water, USP                     40.0    ml      40.0  ml    Propylene Glycol, USP                     5.0     g       5.0   g    Polyethyleneqlycol, (40)                     10.0    g       10.0  g    Hydrogenated Castor Oil    Polyvinylpyrrolidone,                     5.0     g       5.0   g    USP (PVP; K25)    Sodium Benzoate, NF                     0.15    g       0.15  g    Saccharin Sodium, USP                     0.5     g       0.5   g    Monoammonium     1.0     g       1.0   g    Glycyrrhizinate    (10% solids).sup.3    Flavors          q.s             q.s    Colorants        q.s             q.s    Liquid Fructose  q.s             q.s    (77.0-77.5% solids)    ______________________________________     .sup.1 Riboflavin content     .sup.2 Iron content     .sup.3 A 10% solids solution in glycerin or propylene glycol from     MacAndrews & Forbes Co.

Purified water, USP purged with nitrogen was added t o a closed vesselwhose headspace was also purged with nitrogen. To that water was addedFerrous Sulfate dried, USP with mixing for one hour. The Povidone 25,USP was thereafter added with mixing until all particles were dissolved.A first portion of the Liquid Fructose solution (about 20% of the total)was then admixed to homogeneity, followed by admixture of Ascorbic Acid,USP with mixing until all of the particles were dissolved. Thereafter,Niacinamide, USP, Pyridoxine Hydrochloride, USP, Thiamine Hydrochloride,USP, and Sodium Saccharin, USP were each added and admixed tohomogeneity in a serial manner. Where vitamin B₁₂ was present in theformula instead of ferrous sulfate, that vitamin was added and admixedto homogeneity after sodium saccharin to complete the preparation ofphase one.

Phase two was formed by seriatim admixture of Sodium Benzoate, USP andRiboflavin Phosphate Sodium, USP to another portion of purified water,USP followed by agitation until all particles were dissolved.

Polyetheleneglycol (40) castor oil was placed in a stainless steelvessel and heated to a temperature of 60° C. with stirring. To thatheated material were serially added Vitamin A Palmitate, USP, Vitamin D₃and Vitamin E Acetate, USP, and each composition formed was agitated atabout 60° C. until an even dispersion of the oil phase was formed.Propylene glycol and a further amount of purified water, USP wereadmixed, heated to a temperature of 60° C., and then slowly admixed withthe oil phase at a temperature of approximately 60° C. to form phasethree.

Phases one and three were blended at an initial temperature of about 55°C. Agitation was discontinued and about 2/3 of the total liquid fructosewas admixed, followed by the flavorant that was added with agitation andthen the Magnasweet that was also added with agitation. Phase two wasthereafter added with agitation to the composition and the finaldilution of the composition was made with a necessary amount of theliquid fructose that was added in the absence of agitation. Agitationwas resumed to achieve homogeneity and a final pH value of 3.3.

The foregoing description and the examples are intended as illustrativeand are not to be taken as limiting. Still other variations within thespirit and scope of this invention are possible and will readily presentthemselves to those skilled in the art.

We claim:
 1. A liquid pharmaceutical composition comprising apharmaceutically effective amount of a bitter-tasting drug dissolved ordispersed in an aqueous medium that is free of ethanol, said aqueousmedium consisting essentially of water, about 5 to about 30 weightpercent polyvinylpyrrolidone, about 35 to about 55 weight percent of aC₃ -C₆ polyol, about 0.01 to about 0.5 weight percent ammoniumglycyrrhizinate and one or more flavorants, said liquid compositionbeing transparent and having a pleasant taste when administered orally,wherein said bitter-tasting drug is selected from the group consistingof a vitamin preparation and minerals.
 2. The liquid pharmaceuticalcomposition according to claim 1 wherein said polyvinylpyrrolidone ispresent at about 7 to about 15 weight percent.
 3. The liquidpharmaceutical composition according to claim 1 wherein said C₃ -C₆polyol is present as a mixture of C₃ polyols and C₆ polyols.
 4. Theliquid pharmaceutical composition according to claim 1 wherein saidammonium glycyrrhizinate is present at a weight ratio to said drug ofabout 1:50 to 2:1.
 5. The liquid pharmaceutical composition according toclaims 1 wherein said drug is present in an amount of about 0.5 to about5 weight percent.
 6. A liquid pharmaceutical composition comprisingabout 0.5 to about 5 weight percent of a bitter-tasting drug dissolvedor dispersed in an aqueous medium that is free of ethanol, said aqueousmedium consisting essentially of water, about 7 to about 15 weightpercent polyvinylpyrrolidone, about 45 to about 55 weight percent of aC₃ -C₆ polyol, about 0.01 to about 0.5 weight percent ammoniumglycyrrhizinate and one or more flavorants, said ammoniumglycyrrhizinate being present at a weight ratio to said drug of about1:50 to about 1:10 and said liquid composition being transparent andhaving a pleasant taste when administered orally, wherein saidbitter-tasting drug is selected from the group consisting of a vitaminpreparation or minerals.
 7. The liquid pharmaceutical compositionaccording to claim 6 wherein said C₃ -C₆ polyol is present as a mixtureof C₃ polyols and C₆ polyols.
 8. The liquid pharmaceutical compositionaccording to claim 7 wherein the weight ratio of said C₃ polyol to saidC₆ polyol is about 1:4 to about 3:5.
 9. The liquid pharmaceuticalcomposition according to claim 6 wherein polyol other than a C₆ polyolconstitutes less than about 5 weight percent of said composition. 10.The liquid pharmaceutical composition according to claim 6 wherein saiddrug is present in an amount of about one to about 3 weight percent. 11.The liquid pharmaceutical composition according to claim 6 wherein saidC₃ -C₆ polyol is present at about 45 to about 55 weight percent.
 12. Theliquid pharmaceutical composition according to claim 6 wherein saidammonium glycyrrhizinate is present at a weight ratio to said drug ofabout 1:50 to about 1:10.
 13. A liquid pharmaceutical compositioncomprising a pharmaceutically effective amount of trimethoprim dissolvedor dispersed in an aqueous medium that is free of ethanol, said aqueousmedium consisting essentially of water, about 7 to about 15 weightpercent polyvinylpyrrolidone, about 45 to about 55 weight percent of aC₃ -C₆ polyol, about 0.01 to about 0.5 weight percent ammoniumglycyrrhizinate and one or more flavorants, said liquid compositionbeing transparent and having a pleasant taste when administered orally.14. The liquid pharmaceutical composition according to claim 13 whereinsaid C₃ -C₆ polyol is present as a mixture of C₃ polyols and C₆ polyols.15. The liquid pharmaceutical composition according to claim 1 whereinsaid ammonium glycyrrhizinate is present at a weight ratio to saidtrimethoprim of about 1:50 to 1:10.
 16. The liquid pharmaceuticalcomposition according to claim 13 wherein said trimethoprim is presentin an amount of about 0.5 to about 5 weight percent.
 17. A liquidpharmaceutical composition comprising about 0.5 to about 5 weightpercent of trimethoprim dissolved or dispersed in an aqueous medium thatis free of ethanol, said aqueous medium consisting essentially of water,about 7 to about 15 weight percent polyvinylpyrrolidone, about 45 toabout 55 weight percent of a C₃ -C₆ polyol, about 0.01 to about 0.5weight percent ammonium glycyrrhizinate and one or more flavorants, saidammonium glycyrrhizinate being present at a weight ratio to saidtrimethoprim of about 1:50 to about 1:10 and said liquid compositionbeing transparent and having a pleasant taste when administered orally.18. The liquid pharmaceutical composition according to claim 17 whereinsaid C₃ -C₆ polyol is present as a mixture of C₃ polyols and C₆ polyols.19. The liquid pharmaceutical composition according to claim 17 whereinthe weight ratio of said C₃ polyol to said C₆ polyol is about 1:4 toabout 3:5.
 20. The liquid pharmaceutical composition according to claim17 wherein a polyol other than a C₆ polyol constitutes less than about 5weight percent of said composition.
 21. The liquid pharmaceuticalcomposition according to claim 17 wherein said trimethoprim is presentin an amount of about one to about 3 weight percent.
 22. A liquidpharmaceutical composition comprising a pharmaceutically effectiveamount of guaifenesin dissolved or dispersed in an aqueous medium thatis free of ethanol, said aqueous medium consisting essentially of water,about 7 to about 15 weight percent polyvinylpyrrolidone, about 45 toabout 55 weight percent of a C₃ -C₆ polyol, about 0.01 to about 0.5weight percent ammonium glycyrrhizinate and one or more flavorants, saidliquid composition being transparent and having a pleasant taste whenadministered orally.
 23. The liquid pharmaceutical composition accordingto claim 22 wherein said C₃ -C₆ polyol is present as a mixture of C₃polyols and C₆ polyols.
 24. The liquid pharmaceutical compositionaccording to claim 22 wherein said ammonium glycyrrhizinate is presentat a weight ratio to said guaifenesin of about 1:50 to 1:10.
 25. Theliquid pharmaceutical composition according to claim 22 wherein saidguaifenesin is present in an amount of about 0.5 to about 5 weightpercent.
 26. A liquid pharmaceutical composition comprising about 0.5 toabout 5 weight percent of guaifenesin dissolved or dispersed in anaqueous medium that is free of ethanol, said aqueous medium consistingessentially of water, about 7 to about 15 weight percentpolyvinylpyrrolidone, about 45 to about 55 weight percent of a C₃ -C₆polyol, about 0.01 to about 0.5 weight percent ammonium glycyrrhizinateand one or more flavorants, said ammonium glycyrrhizinate being presentat a weight ratio to said guaifenesin of about 1:50 to about 1:10 andsaid liquid composition being transparent and having a pleasant tastewhen administered orally.
 27. The liquid pharmaceutical compositionaccording to claim 26 wherein said C₃ -C₆ polyol is present as a mixtureof C₃ polyols and C₆ polyols.
 28. The liquid pharmaceutical compositionaccording to claim 26 wherein the weight ratio of said C₃ polyol to saidC₆ polyol is about 1:4 to about 3:5.
 29. The liquid pharmaceuticalcomposition according to claim 6 wherein polyol other than a C₆ polyolconstitutes less than about 5 weight percent of said composition. 30.The liquid pharmaceutical composition according to claim 26 wherein saidguaifenesin is present in an amount of about one to about 3 weightpercent.